1. Technical Field
The present disclosure relates to the use of a nitroaniline derivative for the production of nitric oxide, in particular in the preparation of a medicament for treating diseases wherein the administration of nitric oxide may be beneficial. The present disclosure further relates to a kit comprising a nitroaniline derivative and to a system for the production of nitric oxide.
2. Description of the Related Art
Nitric oxide (NO) has been shown to play a significant role in the regulation of many biochemical pathways in organisms (“Nitric oxide: Physiology, Pathophysiology, and Pharmacology”, M. Moncada et al, Pharmacological Review, vol. 43(2), pages 109-142, 1991 and “Biosynthesis and Metabolism of Endothelium-derived Nitric Oxide”, L. J. Ignarro, Ann. Rev. Pharmacol. Toxicol., vol. 30, pages 535-560, 1990). Nitric oxide has been proven to be an important modulator of vascular, cardiovascular, nervous and immune systems as well as other homeostatic mechanisms (“Inhaled Nitric Oxide: A selective pulmonary vasodilator reversing human hypoxic K pulmonary vasoconstriction (HPV)”, Z. Blomquist, Circulation, vol. 84, No. 4, page 361, 1991 and “Involvement of nitric acid in the reflex relaxation of the stomach to accommodate food or fluid”, K. M. Desai et al., Nature, vol. 351, No. 6, page 477, 1991). Desai et al demonstrated that adaptive relaxation in isolated stomach of the guinea pig is mediated by a non-adrenergic, non-cholinergic (NANC) neurotransmitter. Furthermore, they showed that this NANC neurotransmitter is undistinguishable from nitric oxide derived from L-arginine. The authors concluded that it is likely that nitric oxide is a final common mediator of smooth muscle relaxation.
Smooth muscles are present, for example, in the walls of the blood vessels, bronchi, gastrointestinal tract, and urogenital tract. Administration of nitric oxide gas to the lung by inhalation could produce localized smooth muscle relaxation without systemic side effects. This characteristic can be used in medicine to treat bronchial constriction and pulmonary hypertension, pneumonia, etc.
To date, conventional treatment of pulmonary and cardiovascular abnormalities has primarily involved the use of bronchodilators drugs.
Bronchodilators, such as beta-agonists and anticholinergic drugs, are used to reduce airway reactivity and to reverse bronchospasm caused by a variety of diseases, such as asthma, exacerbations of chronic pulmonary obstructive disease, allergic and anaphylactic reactions and others.
Beta-agonists induce bronchodilation by stimulating receptors that increase adenyl cyclase concentrations and the production of intracellular cyclic adenosine monophosphate (AMP). They can be delivered by aerosol, orally or parenterally. Administration of these agents causes significant adverse cardiac effects such as tachycardia, heart palpitations, changes in blood pressure and also other side effects including anxiety, tremors, nausea and headaches. Newer beta2-selective agonists have fewer side effects and somewhat slower onset of action.
Anticholinergic drug, administered by aerosol, are effective bronchodilators with relatively few side effects. However, they have a slow onset of action, and 60 to 90 minutes may be required before peak bronchodilation is achieved.
Nitric oxide is unique in that it combines a rapid onset of action occurring within seconds with the absence of systemic effects. Once inhaled, it diffuses through the pulmonary vasculature into the bloodstream, where it is rapidly inactivated by combination with hemoglobin. Therefore, the bronchodilator effects of inhaled nitric oxide are limited to the airway and the vasodilatory effects of inhaled nitric oxide are limited to the pulmonary vasculature.
The usage of inhaled NO gas as a selective therapeutic agent for the treatment of pulmonary and cardiovascular ailments is also reported in “Inhaled nitric oxide as a cause of selective pulmonary vasoldilation in pulmonary hypertension”, J. Perke-Zaba et al, The Lancet, vol. 338, No. 9, page 1173, 1991. It has recently been established that the administration of 5 to 80 ppm of NO in respiratory gases drastically improves persistent pulmonary hypertension of newborn children within a few minutes. This important medical application of NO gas is discussed in “Inhaled nitric oxide in persistent pulmonary hypertension of the newborn” by J. D. Roberts et al., The Lancet, vol. 340, pages 818-819, 1992.
In addition to these effects, NO has also been reported to act as efficient anticancer agent that inhibits key metabolic pathways to block the growth of or to kill cells (C. M. Maragos, J. M. Wang, J. A. Hrabie, J. J. Oppenheim, L. K. Keefer, Cancer Res. 1993, vol. 53, page 564; J. B. Mitchell, D. A. Wink, W. DeGraff, J. Gamson, L. K. Keefer, M. C. Krishna, Cancer Res. 1993, vol. 53, page 5845; L. Li, R. G. Kilbourn, J. Adams, I. J. Fidler, Cancer Res. 1991, vol. 52, page 2531; R. J. Griffin, C. W. Song, Presented at the 43rd Annual Meeting of the Radiation Research Society, San Jose, Calif., April 1995; Abstract P15-204; D. Moncada, D. Lekieffre, B. Arvin, B. Meldrum, Neuroreports 1993, vol. 343, page 530; D A Wink, Y Vodovotz, J Laval, F Laval, M W Dewhirst, and JB Mitchell, Carcinogenesis vol. 19, no. 5, page 711-721, 1998).
The failure of NO therapy to achieve widespread usage is primarily attributable to the previous lack of a precision NO gas generator suitable for clinical and biomedical applications.
It is known to produce NO through different methods such as thermal methods, electrochemical methods or photochemical methods.
Molecular systems useful in thermal methods are extensively studied in the literature (Peng George Wang, Ming Xian, Xiaoping Tang, Xuejun Wu, Zhong Wen, Tingwei Cai, and Adam J. Janczuk, Chem. Rev. 2002, vol. 102, pages 1091-134; Zhelyaskov, V. R., Godwin, D. W., and Gee, K., Photochem. Photobiol., 1998, vol. 67, pages 282-288). The main disadvantage of these methods is that the NO release is not controllable and can not be achieved on demand.
Therefore, the implementation of these methods in medical device is not suitable and to date it does not exist in any medical device based on such methods.
Electrochemical and electrical methods allow accurate delivery of variable concentrations of NO upon electrical stimuli. They can allow a controllable on demand release of NO.
However, the implementation of these methods in devices for medical applications gives rise to complex systems, often not applicable to clinical or home use and in some cases based on process susceptible to fluctuations in internal and external operating parameters.
In this context, historically NO gas has been commercially manufactured using the well-known Ostwald process in which ammonia is catalytically converted to NO and nitrous oxide at a temperature above 800 DEG C. The Ostwald process is discussed in U.S. Pat. Nos. 4,272,336; 4,774,069 and 5,478,549. The Ostwald process, while suitable for the mass production of NO at high temperatures in an industrial setting, is clearly not applicable to clinical or home use. Other methods of NO gas generation are based on Haber-Bosch synthesis, as described in U.S. Pat. No. 4,427,504, or by taking advantage of paramagnetic properties of nitrous oxide, as described in U.S. Pat. No. 4,139,595.
None of these techniques is suitable for clinical or home use and significant industrial application thereof has not been reported. Yet another method for the generation of NO, which has found limited use in analytical laboratories, relies upon the reaction of 8 molar nitric acid with elemental copper. This method is described by F. A. Cotton in the text “Advanced Inorganic Chemistry”, 5th edition, pages 321-323, John Wiley & Sons, New York, 1988.
There have been recent attempts to devise apparatus for accurately delivering variable concentrations of NO.
By way of example, U.S. Pat. No. 5,396,882 describes a proposal for the generation of NO in an electric discharge in air. In the implementation of this proposed technique, electrodes would be separated by an air gap in an arc chamber. The establishment of a high voltage across the air gap would produce a localized plasma for breaking down oxygen and nitrogen molecules and thereby generate a mixture of NO, ozone and other NOx species. In theory, the concentration of NO could be varied by adjusting the operating current. The gas mixture produced by the process would be purified and mixed with air in order to obtain therapeutically significant concentrations of NO for administration to a patient. The process proposed in U.S. Pat. No. 5,396,882 would, however, inherently be susceptible to fluctuations in internal and external operating parameters, particularly the ambient humidity. Since the therapeutically useful range of NO concentration is relatively small, it is imperative that the concentration of administered NO be precisely controlled. In the process of U.S. Pat. No. 5,396,882, for example, the achievement of such control would dictate that the NO concentration be closely monitored at all times. Since the weight of NO generated by the process of U.S. Pat. No. 5,396,882 will vary with fluctuations in operating parameters, the monitoring of NO concentration would, at best, be extremely difficult and expensive to achieve. Indeed, a chemiluminescence analyzer would have to be incorporated into the apparatus and the size and cost of such an analyzer would adversely affect the cost and portability of the apparatus.
U.S. Pat. No. 5,827,420 describes an electrochemical process based on the production of NO through the coulometric reduction of copper (II) ions (Cu2+) in a solution of nitric acid accompanied by purging the reaction chamber with an inert gas such as nitrogen. The method permits precise control over the rate of production of nitric oxide and can be used for free-standing, portable coulometric generator of controllable amounts of high purity nitric oxide. Nevertheless, such an apparatus is a complex system (several reaction cells, cylinder for carrier gas) that needs the presence of several toxic solutions at high concentration (8M nitric acid, 0.1 CuSO4).
Photochemical methods allow the release of NO in a controllable and precise way on demand upon light stimuli. There are a limited number of compounds able to generate NO using light as trigger that are known in the state of the art (Bordini J., Hughes D. L., Da Motta Neto J. D., Jorge da Cunha C., Inorg. Chem., 2002, vol. 41(21), pages 5410-5416; G. Stochel, A. Wanat, E. Kulis, Z. Stasicka, Coord. Chem. Rev., 1998, vol. 171, pages 203-220; S. Wecksler, A. Mikhailovsky, P. C. Ford, J. Am. Chem. Soc., 2004, vol. 126, pages 13566-13567; J. Baurassa, W. DeGraff, S. Kudo, D. A. Wink, J. B. Mitchell, P. C. Ford, J. Am. Chem. Soc. 1997, vol. 119, page 2853; K. M. Miranda, X. Bu, I. Lorkovic, P. Ford, Inorg. Chem. 1997, vol. 36, page 4838; V. R. Zhelyaskov, K. R. Gee, D. W. Godwin, Photochem. Photobiol. 1998, vol. 67, page 282; L. R. Makings, R. Y. Tsien, J. Biol. Chem. 1994, vol. 269, page 6282; D. J. Sexton, A. Muruganandam, D. J. McKenney, B. Mutus, Photochem. Photobiol., 1994, vol. 59, page 463; M. C. Frost, M. E. Meyerhoff, J. Am. Chem. Soc. 2004, vol. 126, pages 1348-1349; T. Suzuki, O, Nagae, Y. Kato, H. Nakagawa, K. Fukuhara, N. Miyata, J. Am. Chem. Soc., 2005, vol. 127, pages 11720-11726).
Among these, the majority is activated by light in the ultra-violet (UV)-range that, is not only biologically dangerous, but also requires complex instrumentation and is not suitable to be integrated in miniaturized and portable devices.
Only limited examples of NO donors activated by visible light are known (Valentin R. Zhelyaskov and Dwayne W. Godwin, “NITRIC OXIDE: Biology and Chemistry”, Vol. 2, No. 6, pages 454-459 (1998); Bordini J., Hughes D. L., Da Motta Neto J. D., Jorge da Cunha C., Inorg. Chem., 2002, vol. 41(21), pages 5410-5416; J. Baurassa, W. DeGraff, S. Kudo, D. A. Wink, J. B. Mitchell, P. C. Ford, J. Am. Chem. Soc. 1997, vol. 119, page 2853). However, their chemical structures are not adequate for easy chemical derivatization in order to allow their assembly onto films and nanoparticles. Moreover, one potential disadvantage of these compounds is related to the toxic effect of their photoproducts. This requires complex apparatus in order to avoid diffusion of the toxic caging moiety.
Finally, it is known to use a compound of Formula
commonly known as Flutamide, for the production of NO via UV-visible light irradiation (S. Sortino, S. Petralia, G. Compagnini, S. Conoci and G. Condorelli, Light-Controlled Nitric Oxide Generation from a Novel Self-Assembled Monolayer on Gold Surface, Angew. Chem. Int. Ed. 2002-41/11, 1914-1917).
Disadvantageously, this compound shows some limitations related to the fact that only a very small portion of its absorption falls in the visible region of the electromagnetic spectrum and therefore long irradiation times and expensive devices are needed to obtain acceptable yields of NO.